Clearance of apoptotic cells: implications in health and disease

Abstract

Recent advances in defining the molecular signaling pathways that regulate the phagocytosis of apoptotic cells have improved our understanding of this complex and evolutionarily conserved process. Studies in mice and humans suggest that the prompt removal of dying cells is crucial for immune tolerance and tissue homeostasis. Failed or defective clearance has emerged as an important contributing factor to a range of disease processes. This review addresses how specific molecular alterations of engulfment pathways are linked to pathogenic states. A better understanding of the apoptotic cell clearance process in healthy and diseased states could offer new therapeutic strategies.

Figure 1.

Stages of apoptotic cell engulfment and associated cell signaling events that regulate each stage. The four stages of apoptotic cell clearance are shown, with some of the specific key signaling players identified. The “find-me” step occurs when apoptotic cells release soluble chemoattractants that promote chemotaxis of phagocytes via corresponding receptors on the phagocyte. The broken line from LPC to G2A indicates uncertainty of direct ligand–receptor interaction. The “eat-me” stage is characterized by the appearance of ligands on the surface of the dying cell that mark it as a target to be engulfed by phagocytes bearing appropriate DAMP or PtdSer recognition receptors. The “engulfment” stage occurs when signaling downstream of the apoptotic cell recognition receptors stimulates Rac-dependent cytoskeletal rearrangement and formation of the phagocytic cup around the target and subsequent internalization. Once fully internalized, the cell corpse undergoes “processing” through the phagolysosomal pathway that results in the degradation and reprocessing of the dead cell material. DAMP, damage-associated molecular patterns; LPC, lysophosphatidylcholine; MBL, mannose-binding lectin; PS, phosphatidylserine.

Figure 2.

Pathogens usurp the ELMO–Dock–Rac engulfment module. Examples of mechanisms whereby microbial pathogens use the ELMO–Dock–Rac module to alter the host cellular response. The area above the broken line shows mechanism of enhanced S. flexneri invasion via IPGB1 interaction with ELMO, leading to enhanced Rac activation and membrane ruffles that serve as entry points for the bacteria. The area below the broken line shows that HIV-1 uses Nef interaction with the ELMO–Dock2 complex to disrupt CXCR4-dependent chemotaxis in CD4+ T cells.